JPS62501703A - Amino-salicylic acid derivatives, their salts, their preparation and pharmaceutical compositions containing them - Google Patents

Amino-salicylic acid derivatives, their salts, their preparation and pharmaceutical compositions containing them

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JPS62501703A
JPS62501703A JP61500163A JP50016386A JPS62501703A JP S62501703 A JPS62501703 A JP S62501703A JP 61500163 A JP61500163 A JP 61500163A JP 50016386 A JP50016386 A JP 50016386A JP S62501703 A JPS62501703 A JP S62501703A
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amino
benzoic acid
hydroxy
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スポルトレツチ、ジアンカルロ
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イタルファルマコ・エッセ・ピ・ア
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid

Abstract

(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

【発明の詳細な説明】 アミノ　−サリチル酸誘導体、その塩、それらの製法およびそれらを含有する医 薬組成物本発明は式（Ｉ）： （式中、ＢｅはイミダゾリウムまたはＣ−もしくはＮ−置換イミダゾリウムカチ オン、リシンまたは類似の塩基性アミノ酸またはメチルグルカミンであり、Ｒは 水素または０１〜Ｃ２５の直鎖アルキル鎖であり、該ｃ１〜Ｃ２５の直鎖アルキ ル鎖は１またはそれ以上の塩素もしくはフッ素原子、フリーの、エーテル化され たもしくはエステル化アミノカルボニル基またはＮ−置換アミノカルボニル基で ケト基で任意に置換されていてもよい：式：（式中、ｎは１〜１０の整数であり 、Ｒ１およびＲ２は同じかまたは異なっていてもよく、水素、ハロゲン、−０Ｒ ３＊たはＣＯＯＩｈ　（式中、Ｒ３は水素またはＣＩ　〜Ｏｓの低級アルキルを あられす））の鎖；式：％式％ （式中、ｍは０〜２ｏの整数であり、１ｌｅｔはピロール−ピ１ノジ′・７ラン ・ピラン・チオフェン、オキサゾール、イソオキサゾール、イミダゾール、ピラ ゾールまたはチアゾール基のような、１またはそれ以上のＮ、　０もしくはＳ原 子を含む任意に置換された５員もしくは６員の複素環基をあられす）の鎖；式： （式中、ｐはθ〜１６の整数である）の鎖；式：（式中、ｑは１〜１６の整数で ある）の鎖；フェニル基、１またはそれ以上のフッ素もしくは塩素原子、フルオ ロアルキル基、アルコキシ基、アルコキシカルボニル基、０１〜Ｃ４の低級アル キル基、アミノ基、ジアルキルアミノ基、水酸基、シアノ基もしくは式：　Ｎ１ ＩＣＯＲ３（式中、Ｒ３は前記と同じ）で置換されたフェニル基、ジフェニル基 またはナフチル基のようなアリールまたはアラルキ（式中、■は前記と同じであ り、Ｒ４は水素または直鎖もしくは分岐鎖状の飽和もしくは不飽和の０１〜Ｃｏ ｏのアルキル基である）の鎖；式： （式中、Ｒｓ、Ｒ６およびＲ７は同じがまたは異なっていてもよく、１１．０Ｒ ３（式中、Ｒ３“は前記と同じ）、ＮｌＩ２　、ＮｌＩＣ０Ｒｚ　、塩素もしく はフッ素原子またはフルオロアルキル基である）の鎖；式： （式中、Ｒ８は水素、低級アルキル基、フッ素またはフルオロアルキル基である ）の鎖；式： （式中、Ｒ３およびｎは前記と同じ、ｎ′は１〜１０の整数、ＸおよびＹは酸素 、チッ素、イオウ原子または０１１２基である）の直鎖または分岐鎖；式°ニ ー（ＣＩ＋２）　−９−１ｈ 「 （式中、ｒは１〜３の整数であり、Ｒ３は前記と同じ）の鎖、アミノ酸残基、す なわちフリーの形かまたはＢＯＣのような従来のアミノ保護基で保護されたし一 ロイシル基、α−Ｌ−グルタミル基またはγ−Ｌ−グルタミル基；Ａｒｇ−Ｐｒ ｏ−Ｄ（ｐｈｃ）鎖などの鎖；または式：であられされるウロン酸残基をあられ す）であられされる（５−アミノ　−２−ヒドロキシ）安息香酸誘導体に関する 。[Detailed description of the invention] Amino-salicylic acid derivatives, their salts, their production methods and medicines containing them Pharmaceutical compositions of the present invention have the formula (I): (In the formula, Be is imidazolium or a C- or N-substituted imidazolium cathode. ion, lysine or similar basic amino acid or methylglucamine, and R is hydrogen or a straight chain alkyl chain of 01 to C25; The chain contains one or more chlorine or fluorine atoms, free or etherified. or an esterified aminocarbonyl group or an N-substituted aminocarbonyl group may be optionally substituted with a keto group: Formula: (wherein n is an integer of 1 to 10; , R1 and R2 may be the same or different, hydrogen, halogen, -0R 3* or COOIh (wherein, R3 is hydrogen or lower alkyl of CI to Os) hail)) chain; formula:% formula% (In the formula, m is an integer from 0 to 2o, and 1let is pyrrole-pyrrole-7-run ・Pyran/thiophene, oxazole, isoxazole, imidazole, pyrazole one or more N, 0 or S radicals, such as zole or thiazole groups chain containing optionally substituted 5- or 6-membered heterocyclic groups; formula: (wherein, p is an integer from θ to 16); Formula: (wherein, q is an integer from 1 to 16); a phenyl group, one or more fluorine or chlorine atoms, fluorine or Loalkyl group, alkoxy group, alkoxycarbonyl group, lower alkyl group of 01 to C4 Kyl group, amino group, dialkylamino group, hydroxyl group, cyano group or formula: N1 Phenyl group, diphenyl group substituted with ICOR3 (wherein R3 is the same as above) or aryl or aralkyl such as naphthyl group (wherein ■ is the same as above) R4 is hydrogen or a linear or branched saturated or unsaturated 01-Co chain of ) which is an alkyl group of o; formula: (wherein Rs, R6 and R7 may be the same or different, 11.0R 3 (in the formula, R3" is the same as above), NlI2, NlIC0Rz, chlorine or is a fluorine atom or a fluoroalkyl group; the formula: (In the formula, R8 is hydrogen, lower alkyl group, fluorine or fluoroalkyl group. ) chain; formula: (In the formula, R3 and n are the same as above, n' is an integer of 1 to 10, X and Y are oxygen , nitrogen, sulfur atom or 0112 group); -(CI+2) -9-1h " (wherein r is an integer of 1 to 3, and R3 is the same as above), amino acid residues, i.e. in free form or protected with a conventional amino protecting group such as BOC. Leucyl group, α-L-glutamyl group or γ-L-glutamyl group; Arg-Pr chains such as o-D (phc) chains; or uronic acid residues of the formula: (5-amino-2-hydroxy)benzoic acid derivatives .

本発明の他の目的は、を効成分として化合物（１）を含有する医薬組成物ととも に、化合物（１）の製法によって゛提供される。Another object of the present invention is to provide a pharmaceutical composition containing compound (1) as an active ingredient. is provided by the method for producing compound (1).

５−（２，４−ジクロロベンゾイルアミノ）−２−ヒドロキシ安息香酸、５−（ シクロへキシルメチルアミノ）−２−ヒドロキシ安息香酸、５−（リルイルアミ ノ）−２−ヒドロキシ安息香酸、５−（アラキシルアミノ）−２−ヒドロキシ安 息香酸、５〜（アラキトニルアミノ）−゛２−ヒドロキシ安息香酸、５−（２， ６または３．５−ジフルオロ−フェニル）−２−ヒドロキシ安息香酸、５−（４ −シクロヘキシル−ブタノイルアミノ）−２−ヒドロキシ安息香酸、５−［２− （３−ピリジル）アセチルアミノコ−２−ヒドロキシ安息香酸、５−［４−（フ ェニル）ベンゾイルアミノコ−２−ヒドロキシ安息香酸、５−（鳳−トリフルオ ロメチル−シンナモイル）−アミノ　−２−ヒドロキシ安息呑ヒドロキシ安息香 酸はそれ自体新規であり、それゆえ薬理学的に許容しうる有機−しくは無機の塩 基との塩およびそれらを含有する医薬組成物と同様に本発明の範囲に含まれる。5-(2,4-dichlorobenzoylamino)-2-hydroxybenzoic acid, 5-( cyclohexylmethylamino)-2-hydroxybenzoic acid, 5-(lylylamine) -2-hydroxybenzoic acid, 5-(araxylamino)-2-hydroxybenzoic acid Zozoic acid, 5-(arachitonylamino)-2-hydroxybenzoic acid, 5-(2, 6 or 3,5-difluoro-phenyl)-2-hydroxybenzoic acid, 5-(4 -cyclohexyl-butanoylamino)-2-hydroxybenzoic acid, 5-[2- (3-pyridyl)acetylaminoco-2-hydroxybenzoic acid, 5-[4-(ph) phenyl)benzoylaminoco-2-hydroxybenzoic acid, 5-(Otori-trifluoro) methyl-cinnamoyl)-amino-2-hydroxybenzoic acid The acid is novel per se and is therefore a pharmacologically acceptable organic- or inorganic salt. Also included within the scope of the invention are salts with the groups and pharmaceutical compositions containing them.

一方、イミダゾール塩（１）はもちろん新規であるが、対応する酸（アニオン成 分）のいくつかは、たとえばヨーロッパ特許出願公開第４５９５５号公報、西ド イツ特許出願公開第２，０３１，２２７号、同第２，９１９，５４５号および同 第２．９２０，２９２号各公報、特開昭５３−９［ｉ５１号公報、バイオケミカ ル　アンド　バイオフィジカル　リサーチ　コミュニケーション（１１１ｏｃｈ ｅＩ１．Ｂｌｏｐｈｙｓ、Ｒｃｓ、Ｃｏｍａｕｎ、）ｖ、１０１ｓ２５Ｂ、およ びバイオメディカル　マス　スペクトロモロジー（旧ｏａｅｄ、Ｍａｓｓ　５ｐ ｅｃｔｒｏｓ、）　、１１、５３９．１９８４から知られている。しかしながら 、それらの薬理作用は記載されていない。On the other hand, imidazole salt (1) is of course new, but the corresponding acid (anionic Some of the Japan Patent Application Publication Nos. 2,031,227, 2,919,545 and No. 2.920, 292, JP-A-53-9 [i51, Biochem. Le and Biophysical Research Communication (111och eI1. Blophys, Rcs, Comaun, )v, 101s25B, and and biomedical mass spectromology (formerly oaed, mass 5p ectros, ), 11, 539.1984. however , their pharmacological effects have not been described.

いまやこれらの知られた化合物もまた驚くべき有利な薬理学的特性を有すること が見出された。It is now clear that these known compounds also have surprising and advantageous pharmacological properties. was discovered.

それゆえ、本発明のさらなる目的は、以下に明確に説明する前記知られた酸を有 効成分として含有する医薬組成物によって提供される。It is therefore a further object of the present invention to contain said known acids as specifically explained below. It is provided by a pharmaceutical composition containing it as an active ingredient.

本発明の化合物の製造は、５−アミノ　−サリチル酸から出発し、これを適当な 溶媒中に任意に希釈し適当な塩基（ピリジン、トリエチルアミンなど）の存在下 で式：ＲＣＯＯＩＩ　（式中、Ｒは前記と同じ）であられされる酸の酸塩化物ま たは酸無水物のような活性誘導体と反応させることによって行なわれる。室温に おいてまたは加熱下に撹拌したのち、Ｎ、０−ジアシル生成物とＮ−アシル生成 物と符表昭６２−５０１７０３　（４） 基自体の性質の両方を防げないようにきわめて穏やかな条件での０−アシル基の 選択的加水分解に供される。該方法は、反応媒質から回収し適当に溶媒中に溶解 させたアシル誘導体混合物を、少量の水の存在下で触媒量のイミダゾール塩基で 処理することによって特徴づけられる〇注目するアシル基にしたがって種々の時 間室温で撹拌したのち、Ｎ−アシル誘導体の回収は溶媒を蒸発させついで適当な 溶媒から再結晶させることによってＮ−アシル誘導体の回収を行なう。The preparation of the compounds of the invention starts from 5-amino-salicylic acid, which is converted into a suitable Arbitrarily diluted in a solvent and in the presence of an appropriate base (pyridine, triethylamine, etc.) Acid chloride or acid chloride of the formula: RCOOII (wherein R is the same as above) or by reacting with an active derivative such as an acid anhydride. to room temperature N,0-diacyl product and N-acyl product after stirring under heating or under heating. Objects and symbols Showa 62-501703 (4) of the 0-acyl group under extremely mild conditions so as not to interfere with both the properties of the group itself. Subjected to selective hydrolysis. The method involves recovering the reaction medium from the reaction medium and dissolving it in a suitable solvent. The prepared acyl derivative mixture was treated with a catalytic amount of imidazole base in the presence of a small amount of water. Characterized by treatment 〇 At various times depending on the acyl group of interest After stirring at room temperature for a while, the N-acyl derivative can be recovered by evaporating the solvent and using a suitable solution. Recovery of the N-acyl derivative is carried out by recrystallization from a solvent.

薬理学的に許容しつる金属または他の有機塩基の塩と同様に、イミダゾールまた は置換イミダゾール塩は、適当な溶媒中で等モル量の対応する酸および塩基を混 合することによって製造される。該塩の回収は、反応媒質から自然に沈澱させる か、真空下で溶媒を蒸発させるか、または混和しうる沈澱用溶媒を媒質自体・に 加えることによって行なわれる。Imidazole or other pharmacologically acceptable salts of metal or other organic bases. The substituted imidazole salt is prepared by mixing equimolar amounts of the corresponding acid and base in a suitable solvent. manufactured by combining. Recovery of the salt allows it to spontaneously precipitate from the reaction medium. or evaporate the solvent under vacuum, or add a miscible precipitation solvent to the medium itself. It is done by adding.

以下の実施例は本発明の範囲を制限することなく本発明をさらに詳しく説明する 。The following examples further illustrate the invention without limiting its scope. .

２．４−ジクロロベンゾイル−クロライド２０．９５　、　（０，１モル）を、 無水ピリジン１５０ｍ１中の５−アミノ　−サリチル酸１５．３１　ｇ　（０， １モル）の溶液に、暗所およびチッ素雰囲気中で撹拌しながらゆっくり加える。2.4-dichlorobenzoyl-chloride 20.95, (0.1 mol), 15.31 g of 5-amino-salicylic acid in 150 ml of anhydrous pyridine (0, 1 mol) solution with stirring in the dark and under nitrogen atmosphere.

つぎに溶液を氷水に注ぎ、減圧下で濾過し、えられた沈澱を中性になるまでイミ ダゾール塩基ｏ、ｓｒを加え、混合物を室温で３時間撹拌する。溶媒を真空下で 留去し、残渣を酢酸エチルで集め取り、酸性）！２０（ＩＣ＆）で洗浄し、つい で水で中性になるまで洗浄し、硫酸ナトリウム上で乾燥する。溶媒を蒸発させた のち、残渣をメタノールから結晶化させて、収量：　１７．４９　ｇ　（５３， ６３％）、融点２３３〜２３５℃；１、Ｒ，：元素分析、実測値（計算値）　： 　Ｃ−５１，７４（５１，５５）　；生成物１　１０ｇ　（３０，８８ミリモル ）をメタノール１００　ｍｌに溶解し、イミダゾール２．０９　ｇ　（３０，Ｈ ミリモル）を加える。混合物を３時間撹拌し、つぎに溶媒を減圧下で除去する。The solution was then poured into ice water, filtered under reduced pressure, and the resulting precipitate was immobilized until neutral. Dazole base o, sr is added and the mixture is stirred at room temperature for 3 hours. Solvent under vacuum Distill and collect the residue with ethyl acetate (acidic)! 20 (IC&) and then Wash with water until neutral and dry over sodium sulfate. the solvent was evaporated Afterwards, the residue was crystallized from methanol, yield: 17.49 g (53, 63%), melting point 233-235°C; 1, R,: elemental analysis, measured value (calculated value): C-51,74 (51,55); Product 1 10 g (30,88 mmol ) was dissolved in 100 ml of methanol, and 2.09 g of imidazole (30, H mmol). The mixture is stirred for 3 hours and then the solvent is removed under reduced pressure.

残渣をメタノール−水から結晶化させる。融点８７〜８９℃、　１．Ｒ，：　３ １４０．１６５０．１５８５．１３２０ｃｍ−１；　［Ｊ、Ｖ、　：２３３．２ ５３．３２５ｒｖ　：元素分析、実測地（計算値）二〇−５０，８３（５１，， ８０）　；　Ｉ＋−３，４７（３，２３）　；　Ｎ−１０，７２（１０，６６） を有する１ａ１０．６５　ｇをつる（８８．１１％）。The residue is crystallized from methanol-water. Melting point: 87-89°C, 1. R: 3 140.1650.1585.1320cm-1; [J, V, :233.2 53.325rv: Elemental analysis, actual measurement location (calculated value) 20-50,83 (51,, 80); I+-3,47 (3,23); N-10,72 (10,66) 1a10.65g with (88.11%).

ジン３００ｍ１に溶解する。０℃に冷却したのち、チッ素雰囲気下および暗所で 、ヘキサデカノイルクロライド４１．２３　ｇ　（０，１５モル）を撹拌しなが らゆっくり加える。Dissolve in 300ml of gin. After cooling to 0℃, under nitrogen atmosphere and in the dark. , while stirring 41.23 g (0.15 mol) of hexadecanoyl chloride. Add slowly.

加え終わると撹拌を３時間続け、混合物を氷水１００　ｍｌに注ぎ、ついで酢酸 エチルで抽出°する。有機相を希塩酸で洗浄し、水および溶媒を減圧下で蒸発さ せる。残渣をア溶媒を蒸発させたのち、残渣を酢酸エチルで処理する。Once the addition was complete, stirring was continued for 3 hours, the mixture was poured into 100 ml of ice water, and then acetic acid was added. Extract with ethyl°. The organic phase was washed with dilute hydrochloric acid and the water and solvent were evaporated under reduced pressure. let After evaporation of the solvent, the residue is treated with ethyl acetate.

有機相を水、希塩酸および水で洗浄し中性にする。硫酸ナトリウム上で乾燥し濾 過したのち、溶液を真空下で蒸発させる。残渣をエタノール／水から結晶化させ る。収量；　２ａｇ　（７２％）。The organic phase is washed neutral with water, dilute hydrochloric acid and water. Dry over sodium sulfate and filter. After evaporation, the solution is evaporated under vacuum. The residue was crystallized from ethanol/water. Ru. Yield: 2ag (72%).

生成物＋１１８５〜１８７℃で融解し、　１．Ｒ，：　３５００．３２９０゜１ ６８０．１６５０．１５４０．１３１００ｇ＋−１；　Ｕ、Ｖ、　：　２２３． ２５０．３２５ｎ■；元素分析、実ＤＩ値（計算値）：　Ｃ−７０，１３（７０ ，５５）　；１１−９．４１（９，５２）　；　Ｎ−３，４２（３，５１１）。Melt the product at +1185-187°C, 1. R: 3500.3290゜1 680.1650.1540.13100g+-1; U, V, : 223. 250.325n; Elemental analysis, actual DI value (calculated value): C-70,13 (70 , 55); 11-9.41 (9,52); N-3, 42 (3,511).

２ａ）イミダゾール塩 ２でえられた化合物１１．７４　ｇ　（３０ミリモル）をアセトン　１００ｍ１ に溶解し、イミダゾール塩基２．０４　ｇ　（３０ミリモル）を加える。室温で ５時間撹拌したのち、溶媒を減圧下で蒸発させ、残渣をメタノール−水から結晶 化させる。2a) Imidazole salt 11.74 g (30 mmol) of the compound obtained in step 2 was added to 100 ml of acetone. and add 2.04 g (30 mmol) of imidazole base. at room temperature After stirring for 5 hours, the solvent was evaporated under reduced pressure and the residue was crystallized from methanol-water. to become

１１．３５　ｇ　（８２，３４９ｃｉ　）かえられる。融点＝１３２〜１３４℃ ；１、Ｒ，：　３３１０．１６５０．１５２５．１３００ｃｍ−’　；　Ｕ、Ｖ 、　：　２３３、２５３．３２５ｒｖ　；元素分析、実測値（計算値）：　Ｃ− ６７，５８（８７，９５）　；１１−８．７８（１１，９９）　；　Ｎ−８，８ ２（９，１４）。11.35 g (82,349 ci) can be exchanged. Melting point = 132-134℃ ;1, R,: 3310.1650.1525.1300cm-'; U, V , : 233, 253.325rv; Elemental analysis, measured value (calculated value): C- 67,58 (87,95); 11-8.78 (11,99); N-8,8 2 (9, 14).

実施例３〜２３ 斜上の同じ方法を用い、適当なアシル誘導体がら出発してつぎの表で報告する化 合物を製造した。Examples 3-23 Using the same method above and starting with the appropriate acyl derivative, the compounds reported in the following table A compound was produced.

ａ）を伴う整数はイミダゾール塩を示し、一方、連続する（ｐｒｏｇｒｅｓｓｌ ｖｅ）整数は遊離の酸を示す。融点は℃で、！。Integer numbers with a) indicate imidazole salts, while continuous (progressl) ve) Integer indicates free acid. The melting point is in °C! .

Ｒ１値はｃｍ　’であられされている。すべての化合物は計算値と一致した元素 分析値を有する。The R1 value is expressed in cm'. All compounds are elements that match calculated values It has an analytical value.

第１表 実施例２４〜２８ 先の主張（ｃｌａｉｍｓ）の同じ方法にしたがって、つぎの５−アシロイル−ア ミノ　−サリチル酸を製造した（１．１？、値はａｍ　’であられされており、 元素分析は一致した）。Table 1 Examples 24-28 Following the same method of the previous claims, the following 5-acyloyl-a Mino-salicylic acid was produced (1.1?, the value is expressed as am', Elemental analysis was consistent).

２４−２−ヒドロキシ−５−（４−シクロへキシル−ブタノイル）３２５０．１ ６８０．１６５０．１５４０、！３１０゜２５−２−ヒドロキシ−５〜（２−（ ３−ピリジル）−アセチル）−アミノ安息香酸；融点：２２１〜２２３℃、　１ ．Ｒ，：　３５１０．３２６０、ｌ　［ｉ　８０’、１６４０．１５４０．１３ ００　。24-2-hydroxy-5-(4-cyclohexyl-butanoyl) 3250.1 680.1650.1540,! 310゜25-2-hydroxy-5~(2-( 3-pyridyl)-acetyl)-aminobenzoic acid; melting point: 221-223°C, 1 ．． R,: 3510.3260, l [i 80', 1640.1540.13 00.

２６−２−ヒドロキシ−５−（４−フェニル−ベンゾイル）−アミノ安息香酸； 融点：１７８〜１８０℃、　１．Ｒ，：　３５２０．３２６０．１６８０、１６ ４０．１５３０．１３００　。26-2-hydroxy-5-(4-phenyl-benzoyl)-aminobenzoic acid; Melting point: 178-180°C, 1. R,: 3520.3260.1680, 16 40.1530.1300.

２７−２−ヒドロキシ−５−（ａ−）リフルオロメチル−シンナモイル）−アミ ノ安息香酸；融点：１６２〜１６８℃；　１．Ｒ，：３５００．３２５０．１６ ６０、ｔｅａ５．１５００．１３００　。27-2-hydroxy-5-(a-)lifluoromethyl-cinnamoyl)-ami Nobenzoic acid; Melting point: 162-168°C; 1. R, :3500.3250.16 60, tea5.1500.1300.

２８−２−ヒドロキシ−５−（ＩＩ−（１−イミダゾリル）−オクタノイル）− アミノ安息香酸；融点＝１８３〜１８６℃、１．Ｒ，：３５１０、３２ＧＯ１１ ６８０，１６３５，１５１０，１３００上記の化合物の他の薬理学的に許容しう る塩に加えて対応するイミダゾリウム塩が斜上の方法にしたがって製造される。28-2-hydroxy-5-(II-(1-imidazolyl)-octanoyl)- Aminobenzoic acid; melting point = 183-186°C, 1. R,:3510,32GO11 680,1635,1510,1300 Other pharmacologically acceptable compounds of the above In addition to the corresponding imidazolium salts, they are prepared according to the above method.

生物学的活性 斜上の化合物を、それらの潜在的な生物学的活性の証イで試験した。biological activity The compounds listed above were tested for evidence of their potential biological activity.

ダイズ（ｓａｙ）リポキシゲナーゼ抑制作用るダイズリポキシゲナ〜ゼに対する 抑制作用の存在を示すことができる。ホ乳類におい・ｃｌこの酵素系はロイコト リエンＡ４およびＢ４におけるアラキドン酸のトランスフォーメーション（ｔｒ ａｎｓｌ’ｏｒｍａｔ［ｏｎ）を促進させる。これらの化合物は基本的にフロゴ シス（Ｎｏｇｏｓｌｓ）に責任があることが示される。すなわち、ロイコトリエ ンＡ４およびＢ４は腸の炎症性の病気およびクローン病における適切な前炎症作 用（ｐｒｏ−１ｎｆ’１ａａｖａｔｏｒｙ　ａｃｔｌｖｌｔｙ）を示す＠ダイズ リポキシゲナーゼ（Ｅ、Ｃ，１，１３，１１，１２）を、アクセルロツＦ　（Ａ ｘｅｌｒｏｄ）　ラの方法（アクセルロッド　ビー（Ａｘｃｌｒｏｄ　Ｂ、）、 チースブラウ　ティー　エイチ（ＣＩ＋ｅｃｓｂｒｏｕｇｂ　Ｔ、Ｉｌ、）およ びラークソ　ニス　（Ｌａａｋｓ。Soybean (say) lipoxygenase inhibitory effect against soybean lipoxygenase The presence of an inhibitory effect can be demonstrated. Mammal odor・Cl This enzyme system is a leukotron Transformation of arachidonic acid in Lien A4 and B4 (tr promote ansl'ormat[on]. These compounds are basically frogo Nogosls are shown to be responsible. That is, Leukotrie A4 and B4 contribute to appropriate pro-inflammatory actions in intestinal inflammatory diseases and Crohn's disease. (pro-1nf'1aavatory actlvlty) @ soybean Lipoxygenase (E, C, 1, 13, 11, 12) was added to Axellotz F (A xelrod) La's method (Axclrod B,), Cheesbrougb T H (CI+ecsbrougb T, Il,) and Laaks.

Ｓ、）、メンツズ　イン　エンジモロジ−（Ｍｃｔｂｏｄｓ　ＩｎＥｎｚｙｉｏ ｌｏｇｙ）　、ＶＯｌ、７１．　４４１頁、１９８１．アカデミツクプレス（Ａ ｃａｄｅｍｉｃ　Ｐｒｅｓｓ）Ｎ、Ｙ、）にしたがい、試験標準としてノルヒド ログアイアレチン酸を用い、アッセイされるべき生成物の存在下および非存在下 において、室温で試験した。S,), Mctbods InEnzyio logic), VOl, 71. 441 pages, 1981. Academic Press (A Norhyde as a test standard according to Academic Press)N,Y,) using logaiaretic acid in the presence and absence of the product to be assayed. Tested at room temperature.

第２表には、非限定的な例として、化合物１．１ａ〜１Ｂ、１８ａでえられた結 果が示されている。Table 2 shows, by way of non-limiting example, the results obtained with compounds 1.1a-1B, 18a. The results are shown.

この表および以下の表において、第２表におけるように、整数は遊離の酸を示し 、一方、文字ａをうしろに伴う整数は対応するイミダゾリウム塩に関する。In this table and the following tables, integer numbers indicate free acid, as in Table 2. , while an integer followed by the letter a relates to the corresponding imidazolium salt.

［以下余白］ 第　２　表 血小板凝集およびトロンボキサン＾２産生に対する作用測定は、ニューシーラン トウサギからえられたクエン酸を加えた（ｃｌｔｒａｔｅｄ）血小板に富んだプ ラズマ（ｐｌａｔｃｌｃｔ−ｒｉｃｈ　ｐｌａｓｍａ）（Ｐ、Ｒ，Ｐ、）を用い たイン　ビトロ試験で行なった。血小板の凝集は、凝集剤としてアラキドン酸０ ．２５ｍＭを用い、ボーン（Ｂｏｒｎ）の方法（ボーンジー　ブイ　アール（Ｂ ｏｒｎ　Ｇ、Ｖ、Ｒ，）　、ネーチャー（Ｎａｔｕｒｅ）、　ＶＯｌ、１６２． ６７）にしたがって行なった。[Margin below] Table 2 Measurement of effects on platelet aggregation and thromboxane^2 production was performed using New Sealan. Citrated platelet rich protein obtained from rabbits. Using plasma (platclct-rich plasma) (P, R, P,) This was done in an in vitro test. Platelet aggregation is achieved using arachidonic acid as an aggregating agent. ．． Using 25mM, Born's method (Born) was used. orn G, V, R,), Nature, VOl, 162. 67).

抑制作用は、ＥＤ５０　（＋ｎＭ）、すなわちアラキドン酸の凝集作用の５０９ ６を中和する（ａｎｔａｇｏｎｉｚｅｓ）投与量として評価した。The inhibitory effect is ED50 (+nM), that is, 509 of arachidonic acid aggregation effect. 6 was evaluated as the antagonizing dose.

トロンボキサン＾２の産生は、モンカダ（Ｍｏｎｃａｄａ）ら（モンカダ　ニス 　（Ｍｏｎｃａｄａ　Ｓ、）、フエレイラ　ニス（Ｖａｎｅ　Ｊ、Ｒ，）　、ア ドバンスト　プロスタグランジン　アンド　トロンボキサンズ　リサーチ（＾ｄ ｖ、Ｐｒｏｓｔ、＆Ｔｈｒｏｍｂｏｘａｎｅｓ　Ｒｅｓ、）、フロリツヒ　ジエ イ　シー（Ｆｒｏｌｌｃｈ　Ｊ、Ｃ，）編、Ｖｏｌ、５．２１１．１９７ｇ、レ イブン　プレス（Ｒａｖｅｎ　Ｐｒｅｓｓ））にしたがったバイオアッセイ試験 によって測定した。アラキドン酸の添加後の計画された時間に、ウサギ大動脈の らせん細片およびラットの前底細片からなる一連の組織（ｔｉｓｓｕｅ　５ｅｑ ｕｅｎｃｅ）　、　（カスケード）でＴＡＸ２産生およびプロスタグランジン様 活性についてＰ、Ｒ，Ｐ、　２００ｇｇをバイオアッセイした。The production of thromboxane^2 was reported by Moncada et al. (Moncada S,), Fuereira varnish (Vane J, R,), Advanced prostaglandin and thromboxane research (＾d V, Prost, & Thromboxanes Res, ), Floritzie Edited by Frollch J, C, Vol. 5.211.197g, Review Bioassay test according to Raven Press) Measured by. At the scheduled time after the addition of arachidonic acid, the rabbit aorta was A series of tissues consisting of spiral strips and rat anterior basal strips (tissue 5 eq. (cascade) and TAX2 production and prostaglandin-like 200 gg of P, R, P was bioassayed for activity.

ＴＸ＾２産生に対する供試化合物の抑制作用は、ＥＤ５０（Ｍ）すなわち組織に 対するＴＸＡ２の中綿作用を減少させうる濃度として評価した。The inhibitory effect of the test compound on TX^2 production is determined by the ED50 (M), that is, the The concentration was evaluated as the concentration that can reduce the batting effect of TXA2 on TXA2.

供試化合物はライフン８０に溶解させ、ＥＤ５０の決定かなしとげられるまで増 加する濃度でＰ、Ｒ，Ｐ、に加えた。The test compound was dissolved in Lifen 80 and increased until the ED50 was determined. added to P, R, P, at the desired concentration.

第３表には、非限定的な例として、本発明の化合物のいくつかを用いてえられた 結果が報告されている。Table 3 shows, by way of non-limiting example, the results obtained using some of the compounds of the invention. Results have been reported.

［以下余白］ 第　３　表 アラキドン酸でひき起こされたものに対する抑制（ＥＤ５０．単位Ｍ）非免疫性 および免疫性炎に対する抗炎症作用１　ラットにおけるカラゲーナンによりひき 起こされた胸膜炎（非免疫外炎） 試験は、ジ　ローザ（Ｄｉ　Ｒｏｓａ）ら（ジ　ローザ　エム（旧Ｒｏｓａ　Ｍ 、）、ジラウンド　ジエイ　ビー（Ｇ　ｌ　ｒｏｕｎｄＪ、Ｐ、）およびライロ ービー　ディーエイ（ＶｉｌｌｏｕｇｈｂｙＤ、＾、）、ジャーナ少　オブ　バ ソロジカル　バクテリオロジー（Ｊ、Ｐａｔｌ＋　Ｂａｃｔ、）、ｖｏｌ、１０ ４．１５．１９７１）にしたがって行なった。[Margin below] Table 3 Inhibition (ED50. unit M) of arachidonic acid-induced non-immune and anti-inflammatory effect on immunoinflammatory inflammation 1. Caused pleurisy (non-immune inflammation) The test was conducted by DiRosa et al. (formerly RosaM). , ), G round J, P, and Lilo VilloughbyD (^,), Jhana Obba Thological Bacteriology (J, Patl+ Bact,), vol, 10 4.15.1971).

０．９％ＮａＣｌ中のカラゲーナンの１９６溶液（０，１５１１１１）を、体重 的２５０ｇのスブラーグードーリ−（Ｓｐｒａｇｕｅ−Ｄａｗｌｅｙ）ラットの 胸膜腔内に注射した。６時間後、動物を層殺し、胸膜腔浸出液容量をＩＩＦ＋定 し、白血球総数をマイクロセルカウンター（ｍ　Ｉｃｒｏ−ｅｅｌ　１−ｃｏｕ ｎｔｅｒ）でカウントし、腔を生理食塩水媒質（ｓａｌｉｎｅ　ｍｅｄｉｕｍ） ０．５ｍｌですすいだ。A 196 solution of carrageenan (0,151111) in 0.9% NaCl was added to the body weight A 250 g Sprague-Dawley rat Injected into the pleural cavity. After 6 hours, the animals were sacrificed and the volume of pleural exudate was determined by IIF+. Then, count the total number of white blood cells using a microcell counter (mIcro-eel 1-cou (inter), and the cavity was filled with saline medium. Rinse with 0.5ml.

白血球総数の％抑制を、コントロールの動物に対して計算した。アッセイする化 合物は、カラゲーナンを胸膜腔中に投与する３０分前に、１ｍＭ／ｋｇを経口で 投与した。第４表には、非限定的な例として、本発明の化合物のいくつかでえら れた結果が報告されている。Percent suppression of total leukocyte counts was calculated relative to control animals. to assay The compound was administered orally at 1mM/kg 30 minutes before administering carrageenan into the pleural cavity. administered. Table 4 shows, by way of non-limiting example, some of the compounds of the invention. The results have been reported.

［以下余白］ 第　４　表 に対する％抑制 ２　ラットの足における予Ｑ　（ｒｅｓｅｒｖｅ）受身アルサス反アッセイは、 ゲメル（ＧｅｍＩＩｅｌ）ら（ゲメル　ディー　ケイ（ＧＯＩＩＩＩＩＩＯＩ　 Ｄ、に、）　、コツトニー　ジエイ（Ｃｏｔｔｎｅｙ　Ｊ、）およびルイス　エ イ　ジエイ（Ｌｅｖｌｓ　Ａ、Ｊ、）、エージエンツアクションズ（Ａｇｅｎｔ ｓ　Ａｃｔｉｏｎｓ）、ｖｏｌ、９．１０７．１９７９）にしたがって行なった 。ウサギの抗ウシアルブミン血清（０，９％ＮａＣｌ　２　ｍｌに溶解させた、 凍結乾燥した抗体）ＩＭｆｉを、雄のスプラーグードーリーラットの尾静脈中に 注射した。[Margin below] Table 4 % suppression for 2 Pre-Q (reserve) passive Arthus counterassay in rat paws GemIIel et al. D., J.), Cottney J., and Lewis E. Levels A, J, Agents Actions s Actions), vol. 9.107.1979). . Rabbit anti-bovine albumin serum (dissolved in 2 ml of 0.9% NaCl, Lyophilized antibody) IMfi was injected into the tail vein of male Sprague-Dawley rats. Injected.

３０分後、ウシアルブミン０．０２５■（生理食塩水０　、１　ｍｌ中）を下方 足底（ｓｔｊｂｐｌａｎｔａｒ　ｐａｗ＞に注射した。５時間後に足の容積を水 銀ブレチスモ計（ＩＩｅｒｃｕｒｙｐｔｅｔｈｙｓｍｏｍｃｔｅｒ）によって測 定した。After 30 minutes, add bovine albumin 0.025■ (in 0.1 ml of physiological saline) downward. The plantar paw was injected. After 5 hours, the volume of the paw was replaced with water. Measured by silver blethysmometer (IIercuryptethysmomcter) Established.

供試化合物は、ウシアルブミンで処理する３時間前に経口投与した。ラットの足 の容積の増加の％抑制を、未処理の動物の足の容積の増加に対して計算した。本 発明の化合物のいくつかでえられた結果が節５表に報告されている。The test compound was orally administered 3 hours before treatment with bovine albumin. rat paw The % inhibition of the increase in volume of was calculated relative to the increase in paw volume of untreated animals. Book Results obtained with some of the compounds of the invention are reported in Section 5 Table.

［以下余白］ 第　５　表 （ｔ）　Ｎａ−５−ＡＳＡ　：　５−アミノサリチル酸ナトリウム塩（）内の数 字はωｇ／ｋｇでの投与量を示す。[Margin below] Table 5 (t) Na-5-ASA: 5-aminosalicylic acid sodium salt (number in parentheses) The letters indicate the dose in ωg/kg.

経口投与は各供試化合物に対し１　ｍＭ／　ｋｇに相当する。Oral administration corresponds to 1 mM/kg for each test compound.

３　ラットにおける酢酸腸炎（非免疫性腸炎）アッセイは、シャロン（Ｓｈａｒ ｏｎ）　（シャロン　ビー（Ｓｈａｒｏｎ、　Ｐ、）、ステンソン　グプリニー 　エフ（ｓｔｅｎｓｏｎＬＩ’、）、ガストロエンテロロジ−（Ｇａｓｔｒｏｅ ｎｔｅｒｏｌｏｇｙ）。3 Acetate enteritis (non-immune enteritis) assay in rats was performed by Shar on) (Sharon, P.), Stenson Gupliny Stenson LI', Gastroenterology terology).

ｖｏｌ、８８．５５．１９８５）にしたがって行なった。Vol. 88.55.1985).

アッセイの性質を考慮に入れて、試験は、先の試験でえられた結果にしたがって 充分吸収されなかった本発明の化合物について主に行なった。しかしながら、す べての請求された誘導体が腸炎およびクローン病の治療に有用に適用されうると いうことは注目されるべきである。Taking into account the nature of the assay, the test should be carried out according to the results obtained in previous tests. This study was conducted mainly for compounds of the present invention that were not sufficiently absorbed. However, all that all claimed derivatives may be usefully applied in the treatment of enteritis and Crohn's disease. That should be noted.

結果はつぎの第６表に報告されている。The results are reported in Table 6 below.

投与された投与量（腸内経由で、腸結紮および酢酸の局所注射のあいだに）は、 カルボキシメチルセルロース中に分散させたすべての供試化合物について０．５ ａ＋Ｍ／ｋｇであった。腫瘍形成指数（ｕｌｃｅｒａｔｉｏｎ　Ｉｎｄｅｘ）の ％減少を、未処理の動物に対して計算した。The dose administered (via the intestine, during intestinal ligation and local injection of acetic acid) was 0.5 for all test compounds dispersed in carboxymethylcellulose It was a+M/kg. Tumor formation index % reduction was calculated relative to untreated animals.

［以下余白］ 急性毒性 液中、経口で、マウスにおける急性毒性試験に倶した。[Margin below] acute toxicity Acute toxicity tests were conducted in mice, both in liquid and orally.

すべてのＬＤ５０はＩＧＯＯ＋ｎｇ／ｋｇよりも高いことがわかった。All LD50s were found to be higher than IGOO+ng/kg.

本発明はまた、化合物（１１およびその対応する遊離の酸の治療剤としての用途 に関連したすべての工業的な応用面にも関する。それゆえ本発明の本質的面は、 通常の賦形剤および／または担体に加えて前もって決定され治療学的にを効なｍ の斜上の化合物の少なくとも１種を有効成分として含有する医薬組成物によって 提供される。The present invention also describes the use of compound (11) and its corresponding free acid as a therapeutic agent. It also concerns all industrial application aspects related to. Therefore, the essential aspects of the invention are: In addition to conventional excipients and/or carriers, a predetermined therapeutically effective By a pharmaceutical composition containing as an active ingredient at least one of the compounds listed above provided.

本発明の組成物は、たとえば錠剤、カプセル剤、シロップ、サシエツト（ｓａｃ ｈｅｔｓ）　、水剤、バイアル、ボトル（ｂｏｔｔｌｅｓ）　、坐剤のかたちで 経口、非経口、直腸経由または局所経由で投与される。The compositions of the invention can be used, for example, in tablets, capsules, syrups, sachets, etc. hets), solutions, vials, bottles, and suppositories. Administered orally, parenterally, rectally or topically.

投与量は患者の体重、年齢および健康状態に依存するであろうが、とにか＜　５ ０−１０００ｍｇ　、　１日に１〜４回の範囲であろう。The dosage will depend on the patient's weight, age and health status, but in any case <5 It will range from 0-1000mg, 1-4 times a day.

手続ネ甫正書（方式） ％式％ １事件の表示 ＰＣＴ／ＥＰ８５１００６４５ ２発明の名称 アミノ−サリチル酸誘導体、その塩、それらの製法およびそれらを含有する医薬 組成物 ３補正をする者 事件との関係　特許出願人 住　所　イタリア共和国、ｌ−２０１２６ミラノ、ビアレ　フルビオ　テスチ、 　３３０ 名　称　イタルファルマコ・エッセ・ピ・ア代表者　デーサンチス、フランチェ スコ国　籍　イタリア共和国 ４代理人　〒５４０ ５補正命令の日付 ６補正の対象 （１）　特許法第１８４条の５第１項の規定による書面の項目２「発明の名称」 の欄 （２）明細書の翻訳文第１頁の「発明の名称」の欄 （３）委任状の訳文の「特許出願人代表者の氏名」の欄 ７補正の内容 （１）　別紙のとおり。Procedural formalities (method) %formula% Display of 1 incident PCT/EP85100645 2. Name of the invention Amino-salicylic acid derivatives, their salts, their production methods and pharmaceuticals containing them Composition 3. Person who makes corrections Relationship to the incident: Patent applicant Address: Viale Fulvio Testi, l-20126 Milan, Republic of Italy. 330 Name: Italpharmaco Esse Pia Representative: De Sanchis, France Nationality of Scots Republic of Italy 4 agents〒540 5 Date of amendment order 6. Subject of correction (1) Item 2 “Name of the invention” in the document pursuant to the provisions of Article 184-5, Paragraph 1 of the Patent Act column (2) “Title of the invention” column on the first page of the translation of the specification (3) “Name of patent applicant representative” column in the translation of the power of attorney 7. Contents of amendment (1) As shown in the attached sheet.

（２）　別紙のとおり。(2) As shown in the attached sheet.

（３）別紙のとおり。(3) As shown in the attached sheet.

（４）代表者資格証明書およびその訳文を補充する。(4) Supplement the representative qualification certificate and its translation.

８添付書類の目録 （１）特許法第１８４条の５第１項の 規定による書面　１通 （２）明細書の翻訳文第１頁　１通 （３）委任状の訳文　１通 国際調査報告 入ＮＮＥＸ　Ｔｏ　Ｔｈｅ：　ＩＮＴＥＦＩＮＡＴＩＯＮＡＬ　５ＥＡＲＣ）’ 、Ｒ″−ＰＯＦＩＴ　ＯＮ8 List of attached documents (1) Article 184-5, Paragraph 1 of the Patent Act 1 document according to regulations (2) Translation of the specification, page 1, 1 copy (3) Translation of power of attorney: 1 copy international search report 入NNEX　To　The：　INTEFINATIONAL　5EARC)' , R″-POFIT ON

Claims (8)

【特許請求の範囲】[Claims] １．式（Ｉ）： （式中、Ｂ■はイミダゾリウムまたはＣ−もしくはＮ−置換イミダゾリウムカチ オン、リシンまたは類似の塩基性アミノ酸またはメチルグルカミンであり、Ｒは 水素またはＣ１〜Ｃ２５の直鎖アルキル鎖であり、該Ｃ１〜Ｃ２５の直鎖アルキ ル鎖は１またはそれ以上の塩素もしくはフッ素原子、フリーの、エーテル化され たもしくはエステル化された水酸基、カルボキシル基、カルボキシアルキル基、 アミノカルボニル基またはＮ−置換アミノカルボニル基で任意に置換されており 、１またはそれ以上の−ＣＨ２−基がケト基で任意に置換されていてもよい；式 ： ▲数式、化学式、表等があります▼ （式中、ｎは１〜１０の整数であり、Ｒ１およびＲ２は同じかまたは異なってい てもよく、水素、ハロゲン、−ＯＲ３またはＣＯＯＲ３（式中、Ｒ３は水素また はＣ１〜Ｃ５の低級アルキルをあらわす））の鎖；式：▲数式、化学式、表等が あります▼ （式中、ｍは０〜２０の整数であり、Ｈｅｔはピロール、ピリジン、フラン、ピ ラン、チオフェン、オキサゾール、イソオキサゾール、イミダゾール、ピラゾー ルまたはチアゾール基のような、１またはそれ以上のＮ、ＯもしくはＳ原子を含 む任意に置換された５員もしくは６員の複素環基をあらわす）の鎖；式：▲数式 、化学式、表等があります▼ （式中、ｐは０〜１６の整数である）の鎖；式：▲数式、化学式、表等がありま す▼ （式中、ｑは１〜１６の整数である）の鎖；フェニル基、１またはそれ以上のフ ッ素もしくは塩素原子、フルオロアルキル基、アルコキシ基、アルコキシカルボ ニル基、Ｃ１〜Ｃ４の低級アルキル基、アミノ基、ジアルキルアミノ基、水酸基 、シアノ基もしくは式：ＮＨＣＯＲ３（式中、Ｒ３は前記と同じ）で置換された フェニル基、ジフェニル基またはナフチル基のようなアリールまたはアラルキル 残基；式： ▲数式、化学式、表等があります▼ （式中、ｍは前記と同じであり、Ｒ４は水素または直鎖もしくは分岐鎖状の飽和 もしくは不飽和のＣ１〜Ｃ２０のアルキル基である）の鎖；式：▲数式、化学式 、表等があります▼ （式中、Ｒ５、Ｒ６およびＲ７は同じかまたは異なっていてもよく、Ｈ、ＯＲ３ （式中、Ｒ３は前記と同じ）、ＮＨ２、ＮＨＣＯＲ３、塩素もしくは、フッ素原 子またはフルオロアルキル基である）の鎖；式： ▲数式、化学式、表等があります▼ （式中、Ｒ８は水素、低級アルキル基、フッ素またはフルオロアルキル基である ）の鎖；式：▲数式、化学式、表等があります▼ （式中、Ｒ３およびｎは前記と同じ、ｎ′は１〜１０の整数、ＸおよびＹは酸素 、チッ素、イオウ原子またはＣＨ２基である）の直鎖または分岐鎖；式：−（Ｃ Ｈ２）ｒ−Ｓ−Ｒ３ （式中、ｒは１〜３の整数であり、Ｒ３は前記と同じ）の鎖；アミノ酸残基、す なわちフリーの形かまたはＢＯＣのような従来のアミノ保護基で保護されたレー ロイシル基、α−Ｌ−グルタミル基またはγ−Ｌ−グルタミル基；Ａｒｇ−Ｐｒ ｏ−Ｄ（ｐｈｅ）鎖などの鎖；または式：▲数式、化学式、表等があります▼ま たは▲数式、化学式、表等があります▼のウロン酸残基をあらわす）であらわさ れる化合物。1. Formula (I): (wherein B■ is imidazolium or C- or N-substituted imidazolium cathode) ion, lysine or similar basic amino acid or methylglucamine, and R is hydrogen or a C1-C25 straight-chain alkyl chain, and the C1-C25 straight-chain alkyl chain The chain contains one or more chlorine or fluorine atoms, free or etherified. or esterified hydroxyl group, carboxyl group, carboxyalkyl group, optionally substituted with an aminocarbonyl group or an N-substituted aminocarbonyl group , one or more of the -CH2- groups may be optionally substituted with a keto group; : ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n is an integer from 1 to 10, and R1 and R2 are the same or different. hydrogen, halogen, -OR3 or COOR3 (wherein R3 is hydrogen or represents C1 to C5 lower alkyl chain; Formula: ▲ Numerical formula, chemical formula, table, etc. Yes▼ (In the formula, m is an integer from 0 to 20, and Het is pyrrole, pyridine, furan, pyrrole, Ran, thiophene, oxazole, isoxazole, imidazole, pyrazole containing one or more N, O or S atoms, such as a metal or a thiazole group. (representing an optionally substituted 5- or 6-membered heterocyclic group); Formula: ▲Math. , chemical formulas, tables, etc.▼ Chain of (in the formula, p is an integer from 0 to 16); Formula: ▲There are mathematical formulas, chemical formulas, tables, etc. S▼ (wherein q is an integer from 1 to 16); a phenyl group, one or more phenyl groups; Fluorine or chlorine atom, fluoroalkyl group, alkoxy group, alkoxycarbo Nyl group, C1-C4 lower alkyl group, amino group, dialkylamino group, hydroxyl group , substituted with a cyano group or the formula: NHCOR3 (wherein R3 is the same as above) Aryl or aralkyl such as phenyl, diphenyl or naphthyl Residue; Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, m is the same as above, and R4 is hydrogen or a linear or branched saturated or an unsaturated C1-C20 alkyl group) chain; formula: ▲ mathematical formula, chemical formula There are tables, etc.▼ (In the formula, R5, R6 and R7 may be the same or different, H, OR3 (In the formula, R3 is the same as above), NH2, NHCOR3, chlorine or fluorine source or fluoroalkyl group); formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R8 is hydrogen, lower alkyl group, fluorine or fluoroalkyl group. ) Chain; Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R3 and n are the same as above, n' is an integer of 1 to 10, X and Y are oxygen , nitrogen, sulfur atom or CH2 group; formula: -(C H2) r-S-R3 (wherein r is an integer of 1 to 3, R3 is the same as above); amino acid residue, i.e. in free form or as a ray protected with a conventional amino protecting group such as BOC. Leucyl group, α-L-glutamyl group or γ-L-glutamyl group; Arg-Pr Chains such as o-D (phe) chains; or formulas: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼representing the uronic acid residue) compound. ２．Ｂがイミダゾリウムまたは２−アミノイミダゾリウムである請求の範囲第１ 項記載の化合物。2. Claim 1, wherein B is imidazolium or 2-aminoimidazolium Compounds described in Section. ３．Ｂがイミダゾリウム残基であり、アニオン成分が２−ヒドロキシ−５−（２ ．４−ジクロロベンゾイル）アミノ−安息香酸、２−ドロキシ−５−ヘキサデカ ノイルーアミノ−安息香酸、２−ヒドロキシ−５−イソバレロイル−アミノ−安 息香酸、２−ヒドロキシ−５−シクロヘキシルアセチル−アミノ−安息香酸、２ −ヒドロキシ−５−スクシノイル−アミノ−安息香酸、２−ヒドロキシ−５−ベ ンゾイル−アミノ−安息香酸、２−ヒドロキシ−５−サリシロイル−アミノ−安 息香酸、２−ヒドロキシ−５−〔４−（２′，４′−ジフルオロフェニル）サリ シロイル−アミノ］−安息香酸、２−ヒドロキシ−５−（Ｎ−エトキシカルボニ ル）グリシル）−アミノ−安息香酸、２−ヒドロキシ−５−［（６−エトキシカ ルボニルアミノ）カプロピルアミノ］−安息香酸、２−ヒドロキシ−５−（Ｎ− エトキシカルボニルグルタモイルアミノ）−安息香酸、２−ヒドロキシ−５−グ ルクロニル−アミノ−安息香酸、２−ヒドロキシ−５−ホルミル−アミノ−安息 香酸、２−ヒドロキシ−５−ステアロイル−アミノ−安息香酸、２−ヒドロキシ −５−（４−メトキシ）ベンゾイル−アミノ−安息香酸、２−ヒドロキシ−５− （４−エプチロキシ）ベンゾイル−アミノ−安息香酸、２−ヒドロキシ−５−（ ４−フルオロ）ベンゾイル−アミノ−安息香酸、２−ヒドロキシ−５−アセチル −アミノ−安息香酸、２−ヒドロキシ−５−リノレイル−アミノ−安息香酸、２ −ヒドロキシ−５−アラキジル−アミノ−安息香酸、２−ヒドロキシ−５−アラ キドニル−アミノ−安息香酸、２−ヒドロキシ−５−（２，６−ジフルオロ）ベ ンゾイル−アミノ−安息香酸、２−ヒドロキシ−５−（３，５−ジフルオロ）ベ ンゾイル−アミノ−安息香酸、２−ヒドロキシ−５−（４−シクロヘキシル−ブ タノイル）−アミノ−安息香酸、２−ヒドロキシ−５−（２−（３−ピリジル） −アセチル）−アミノ−安息香酸、２−ヒドロキシ−５−（４−フェニル−ベン ゾイル）−アミフ−安息香酸、２−ヒドロキシ−５−（ｍ−トリフルオロメチル −シンナモイル）−アミノ−安息香酸、２−ヒドロキシ−５−（８−（１−イミ ダゾリル）−オクタノイル）−アミノ−安息香酸、Ｌ−ロイシル−５−アミノ− サリチル酸、γ−Ｌ−グルタミル−５−アミノ−サリチル酸およびアセトアセチ ル−５−アミノ−サリチル酸よりなる群から選ばれたものである請求の範囲第１ 項記載の化合物。3. B is an imidazolium residue, and the anion component is 2-hydroxy-5-(2 ．． 4-Dichlorobenzoyl)amino-benzoic acid, 2-droxy-5-hexadeca Neuro-amino-benzoic acid, 2-hydroxy-5-isovaleroyl-amino-benzoic acid Zozoic acid, 2-hydroxy-5-cyclohexylacetyl-amino-benzoic acid, 2 -Hydroxy-5-succinoyl-amino-benzoic acid, 2-hydroxy-5-benzoic acid 2-hydroxy-5-salicyloyl-amino-benzoic acid, 2-hydroxy-5-salicyloyl-amino-benzoic acid Zozoic acid, 2-hydroxy-5-[4-(2',4'-difluorophenyl)sali Siloyl-amino]-benzoic acid, 2-hydroxy-5-(N-ethoxycarbonylate) glycyl)-amino-benzoic acid, 2-hydroxy-5-[(6-ethoxylic acid) rubonylamino)capropylamino]-benzoic acid, 2-hydroxy-5-(N- Ethoxycarbonylglutamoylamino)-benzoic acid, 2-hydroxy-5-g Lucronyl-amino-benzoic acid, 2-hydroxy-5-formyl-amino-benzoic acid Froic acid, 2-hydroxy-5-stearoyl-amino-benzoic acid, 2-hydroxy -5-(4-methoxy)benzoyl-amino-benzoic acid, 2-hydroxy-5- (4-epthyloxy)benzoyl-amino-benzoic acid, 2-hydroxy-5-( 4-fluoro)benzoyl-amino-benzoic acid, 2-hydroxy-5-acetyl -amino-benzoic acid, 2-hydroxy-5-linoleyl-amino-benzoic acid, 2 -hydroxy-5-arachidyl-amino-benzoic acid, 2-hydroxy-5-ara Kidonyl-amino-benzoic acid, 2-hydroxy-5-(2,6-difluoro)benzoic acid Zoyl-amino-benzoic acid, 2-hydroxy-5-(3,5-difluoro)benzoic acid Zoyl-amino-benzoic acid, 2-hydroxy-5-(4-cyclohexyl-benzoic acid) tanoyl)-amino-benzoic acid, 2-hydroxy-5-(2-(3-pyridyl) -acetyl)-amino-benzoic acid, 2-hydroxy-5-(4-phenyl-benzoic acid) zoyl)-amif-benzoic acid, 2-hydroxy-5-(m-trifluoromethyl -cinnamoyl)-amino-benzoic acid, 2-hydroxy-5-(8-(1-imino) Dazolyl)-octanoyl)-amino-benzoic acid, L-leucyl-5-amino- Salicylic acid, γ-L-glutamyl-5-amino-salicylic acid and acetoacetate Claim 1 is selected from the group consisting of -5-amino-salicylic acid. Compounds described in Section. ４．新規な化合物としての、２−ヒドロキシ−５−（４−シクロヘキシル−ブタ ノイル）−アミノ−安息香酸、２−ヒドロキシ−５−（２−（３−ピリジル）− アセチル）−アミノ−安息香酸、２−ヒドロキシ−５−（４−フェニル−ベンゾ イル）−アミノ−安息香酸、２−ヒドロキシ−５−（ｍ−トリフルオロメチルー シンナモイル）−アミノ−安息香酸および２−ヒドロキシ−５−（８−（１−イ ミダゾリル）−オクタノイル）−アミノ−安息香酸よりなる群から選ばれた化合 物。4. 2-Hydroxy-5-(4-cyclohexyl-butylene) as a new compound Noyl)-amino-benzoic acid, 2-hydroxy-5-(2-(3-pyridyl)- Acetyl)-amino-benzoic acid, 2-hydroxy-5-(4-phenyl-benzoic acid) yl)-amino-benzoic acid, 2-hydroxy-5-(m-trifluoromethyl- cinnamoyl)-amino-benzoic acid and 2-hydroxy-5-(8-(1-yl) Compound selected from the group consisting of (midazolyl)-octanoyl)-amino-benzoic acid thing. ５．２−ヒドロキシ−５−アミノ−安息香酸を、式：ＲＣＯＯＨ（式中、Ｒは前 記と同じ）であらわされる酸の酸塩化物もしくは酸無水物と反応させ、えられた Ｎ，Ｏ−ジアシル誘導体をイミダゾールの存在下で加水分解し、ついで塩基Ｂと 反応させることを特徴とする式（１）であらわされる化合物の製法。5.2-Hydroxy-5-amino-benzoic acid is synthesized with the formula: RCOOH, where R is obtained by reacting with the acid chloride or acid anhydride of the acid represented by The N,O-diacyl derivative is hydrolyzed in the presence of imidazole and then treated with base B. A method for producing a compound represented by formula (1), which comprises causing a reaction. ６．請求の範囲第１項〜第４項記載の化合物の１種または２種以上を有効成分と して含有する抗炎症、抗凝集および抗血栓作用を有する医薬組成物。6. One or more of the compounds described in claims 1 to 4 are used as active ingredients. A pharmaceutical composition having anti-inflammatory, anti-aggregation and anti-thrombotic effects. ７．少なくとも式： ▲数式、化学式、表等があります▼ （式中、Ｒは前記と同じ）であらわされる化合物または藥理学的に許容しうるそ の塩を有効成分として含有する抗炎症、抗凝集および抗血栓作用を有する医薬組 成物。7. At least the expression: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is the same as above) or a chemically acceptable compound A pharmaceutical composition with anti-inflammatory, anti-aggregation and anti-thrombotic effects containing salts of A product. ８．生きている患者における炎症性、血栓性または過凝集性の状態の治療方法で あって、請求の範囲第６項〜第７項記載の組成物を該生きている患者に投与する ことを特徴とする治療方法。8. In methods of treating inflammatory, thrombotic or hypercoagulant conditions in living patients and the composition according to claims 6 to 7 is administered to the living patient. A treatment method characterized by:
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